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  An O-Glycosylation of Fibronectin Mediates Hepatic Osteodystrophy Through alpha 4 beta 1 Integrin

Sens, C., Altrock, E., Rau, K., Klemis, V., von Au, A., Pettera, S., et al. (2017). An O-Glycosylation of Fibronectin Mediates Hepatic Osteodystrophy Through alpha 4 beta 1 Integrin. Journal of Bone and Mineral Research, 32(1), 70-81. doi:10.1002/jbmr.2916.

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 Creators:
Sens, Carla1, Author              
Altrock, Eva1, Author              
Rau, Katrin1, Author              
Klemis, Verena1, Author              
von Au, Anja1, Author              
Pettera, Stefan2, Author              
Uebel, Stephan2, Author              
Damm, Timo3, Author
Tiwari, Sanjay3, Author
Moser, Markus4, Author              
Nakchbandi, Inaam A.1, Author              
Affiliations:
1Nakchbandi, Inaam / Translational Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565162              
2Scientific Service Groups, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565170              
3external, ou_persistent22              
4Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              

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Free keywords: PRIMARY BILIARY-CIRRHOSIS; MONOCLONAL-ANTIBODY FDC-6; MESENCHYMAL STEM-CELLS; CHRONIC LIVER-DISEASE; IN-VITRO; ALLOGRAFT RECIPIENTS; OSTEOBLAST FUNCTION; BONE-FORMATION; OSTEOPOROSIS; MATRIXEndocrinology & Metabolism; FIBRONECTIN; HEPATIC OSTEODYSTROPHY; OSTEOBLAST DIFFERENTIATION; INTEGRIN alpha 4 beta 1; OSTEOPOROSIS;
 Abstract: Patients with cholestatic liver disease experience increased fracture risk. Higher circulating levels of a fibronectin isoform called oncofetal fibronectin (oFN) were detected in a subset of such patients. Administering this isoform to mice suppresses osteoblast differentiation and diminishes bone mineral density in vivo, suggesting it is responsible for bone loss in cholestatic liver disease. The aim of this study was to define the mechanism by which oFN affects osteoblast function and evaluate possible modifiers in experimental hepatic osteodystrophy. The fibronectin isoform oFN is characterized by the presence of various glycosylations. In line with this, adding oFN that underwent enzymatic O-deglycosylation to osteoblasts normalized nodule formation in vitro. Of three possible O-glycosylation sites in oFN, only a mutation at AA 33 of the variable region or binding of this glycosylated site with an antibody normalized osteoblast differentiation. Because the responsible site is located in the variable region of fibronectin, which binds to alpha 4 beta 1 or alpha 4 beta 7 integrins, these integrins were evaluated. We show that integrin alpha 4 beta 1 mediates the inhibitory effect of oFN both in vitro as well as in vivo. In a hepatic osteodystrophy mouse model, we demonstrate that liver fibrosis is associated with increased circulating oFN and diminished BMD. In addition, trabecular bone loss induced by oFN injection or fibrosis induction could be prevented by either administering an antibody that binds to alpha 4 integrin (PS/2) or the CS1 peptide, which contains a binding site for alpha 4 beta 1 integrin. In summary, oFN inhibits osteoblast activity. This is because of an O-glycosylation in the variable region that results in decreased integrin-mediated signaling. This deleterious effect can be thwarted by binding alpha 4 beta 1 integrin. Thus, we have characterized the defect and the receptor mediating bone loss in patients with hepatic osteodystrophy and evaluated possible therapeutic interventions in a murine model. (c) 2016 American Society for Bone and Mineral Research.

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Language(s): eng - English
 Dates: 2016-08-032017-01
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000391989400009
DOI: 10.1002/jbmr.2916
 Degree: -

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Title: Journal of Bone and Mineral Research
Source Genre: Journal
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Publ. Info: Malden, MA : Blackwell Science, Inc.
Pages: - Volume / Issue: 32 (1) Sequence Number: - Start / End Page: 70 - 81 Identifier: ISSN: 0884-0431
CoNE: https://pure.mpg.de/cone/journals/resource/954925550337